GLI3
protein-codingGLI family zinc finger 3, the group of Zinc fingers C2H2-type
Gene summary
This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]
- GCPS
- PHS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~303.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008272
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010144
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008287
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007804
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008272
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007804
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0008287
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0008287
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007804
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008272
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008287
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008287
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008266
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0019673
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008708
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008287
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007804
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007804
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008266
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008287
Submitter: ClinGen
*GLI3* was first reported in relation to autosomal dominant GLI3-related Greig Cephalopolysyndactyly Spectrum in 1997 (Kang et al., PMID: 9054938; Radhakrishna et al., PMID: 9354785; and Wild et al., 1997, PMID: 9302279). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in phenotypic variability or inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity, Greig cephalopolysyndactyly syndrome (GCPS; OMIM: 175700) and Acrocallosal Syndrome (ACS). Also, there were no differences in phenotypic variability or inheritance pattern. Thus, the following disease assertions were lumped: Pallister-Hall Syndrome (PHS; OMIM: 146510) and Oral-Facial Digital Syndrome (OFDS). However, GCPS/ACS disease entity was split from the PHS/OFDS disease entity due to differences in molecular mechanism and phenotypic variability. The split curation for PHS/OFDS will be curated separately. 8 variants (missense, frameshift, splicing) that have been reported in at least 6 probands in 4 publications (PMIDs: 22903559, 25606469, 32495660, 34424959) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function (PMID: 22903559). This gene-disease relationship is also supported by experimental evidence (mouse models; PMIDs: 1289066, 1322743, 8387379). Mutant mice display anomalies like preaxial and post axial polydactyly; interfrontal skull bone; and reduced GLI3 expression. In summary, there is definitive evidence supporting the relationship between *GLI3* and autosomal dominant GLI3-related Greig Cephalopolysyndactyly Spectrum. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 3/19/2026 (SOP Version 12).
Inheritance Pattern: AD
Disease ID:MONDO:0008287
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007804
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic
Intervention: Endocrine
Rationale: Urgent treatment for endocrine abnormalities may be required; Surgical interventions related to hypothalamic hamartoma may be indicated
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GLI3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000168.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 16 | 227 | 35 | 278 | ||
| missense | 3 | 10 | 571 | 239 | 20 | 843 |
| nonsense | 46 | 25 | 1 | 72 | ||
| start loss | 1 | 1 | ||||
| frameshift | 91 | 42 | 4 | 1 | 138 | |
| splice donor/acceptor (+/-2bp) | 6 | 8 | 2 | 16 | ||
| Total | 146 | 86 | 594 | 466 | 56 | 1348 |
Highest pathogenic variant AF is 0.0000065711656
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000159.3 | 14 | MANE Select | |
| Ensembl | ENSP00000379258.3 | 14 | MANE Select | |
| Ensembl | ENSP00000503957.1 | 1 | Standard | |
| Ensembl | ENSP00000503957.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gli3 | Danio rerio | Structure: spinal cord Quality: physical object quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Basal cell carcinoma - Homo sapiens (human)
- cAMP signaling pathway - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Hedgehog signaling pathway - Homo sapiens (human)
- HH-Core
Biological Process
- negative regulation of transcription by RNA polymerase II
- metanephros development
- branching involved in ureteric bud morphogenesis
- in utero embryonic development
- positive regulation of neuroblast proliferation
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- chromatin binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
- cilium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000395925
- Coding exons
- 14
- Length
- 276922
- Individuals with no LoFs
- 125741
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 125748
- p
- 0.0000278
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.522 | 932 | 978 | 0.953 | 0.0000656 | 10388 |
| Missense (PolyPhen) | 305 | 382.45 | 0.79748 | 4131 | ||
| Synonymous | -2.02 | 480 | 427 | 1.12 | 0.0000344 | 3218 |
| Loss of Function | 6.17 | 5 | 53.8 | 0.0929 | 0.00000298 | 601 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. The full-length GLI3 form (GLI3FL) after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while GLI3R, its C-terminally truncated form, acts as a repressor. A proper balance between the GLI3 activator and the repressor GLI3R, rather than the repressor gradient itself or the activator/repressor ratio gradient, specifies limb digit number and identity. In concert with TRPS1, plays a role in regulating the size of the zone of distal chondrocytes, in restricting the zone of PTHLH expression in distal cells and in activating chondrocyte proliferation. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'. {ECO:0000269|PubMed:10693759, ECO:0000269|PubMed:11238441, ECO:0000269|PubMed:17764085}.;
- Disease
- DISEASE: Greig cephalo-poly-syndactyly syndrome (GCPS) [MIM:175700]: Autosomal dominant disorder affecting limb and craniofacial development. It is characterized by pre- and postaxial polydactyly, syndactyly of fingers and toes, macrocephaly and hypertelorism. {ECO:0000269|PubMed:10441342, ECO:0000269|PubMed:12414818, ECO:0000269|PubMed:12794692, ECO:0000269|PubMed:9302279}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pallister-Hall syndrome (PHS) [MIM:146510]: An autosomal dominant disorder characterized by a wide range of clinical manifestations. Clinical features include hypothalamic hamartoma, pituitary dysfunction, central or postaxial polydactyly, and syndactyly. Malformations are frequent in the viscera, e.g. anal atresia, bifid uvula, congenital heart malformations, pulmonary or renal dysplasia. {ECO:0000269|PubMed:10441570}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Polydactyly, postaxial A1 (PAPA1) [MIM:174200]: A condition characterized by the occurrence of supernumerary digits in the upper and/or lower extremities. In postaxial polydactyly type A, the extra digit is well-formed and articulates with the fifth or a sixth metacarpal/metatarsal. {ECO:0000269|PubMed:10441570}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Polydactyly, postaxial B (PAPB) [MIM:174200]: A condition characterized by an extra digit in the occurrence of supernumerary digits in the upper and/or lower extremities. In postaxial polydactyly type B the extra digit is not well formed and is frequently in the form of a skin. {ECO:0000269|PubMed:10441570}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Polydactyly preaxial 4 (POP4) [MIM:174700]: Preaxial polydactyly (i.e., polydactyly on the radial/tibial side of the hand/foot) covers a heterogeneous group of entities. In preaxial polydactyly type IV, the thumb shows only the mildest degree of duplication, and syndactyly of various degrees affects fingers 3 and 4. {ECO:0000269|PubMed:10441570}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.107
Intolerance Scores
- LoFtool
- 0.0146
- RVIS EVS
- -1.31
- RVIS percentile EVS
- 4.83
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.865
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |